1. Field of the Invention
This invention relates generally to compositions and methods for the treatment of renal and cardiovascular diseases. In particular, this invention relates to compositions comprising compounds that mimic epoxide metabolites and to methods for the use of such compositions for the treatment of renal or cardiovascular disease and/or related conditions,
2. Background Art
A major cause of morbidity and mortality is the progression of organ damage associated with renal and cardiovascular diseases. The incidence of end-stage renal disease (ESRD) is escalating, and the two main diseases responsible for the increase in ESRD are diabetes and hypertension. In the case of diabetes, unused glucose remaining in the blood damages the nephrons, resulting in diabetic nephropathy. In patients with hypertension, small blood vessels in the kidney may become damaged and then cannot function properly to filter wastes. One contributing factor to end-organ damage is an impaired endothelium. Interestingly, endothelial dysfunction has been touted as a marker for unfavorable cardiovascular prognosis in humans.
Earlier studies have shown that endothelium-derived factors can act on vascular smooth muscle cells to relax or contract arteries. Nitric oxide and prostaglandins are the main products of the endothelial cells that relax the vascular smooth muscle. In addition, the endothelium releases one or more substances that relax vascular smooth muscle cells through membrane hyperpolarization (i.e., endothelium-derived hyperpolarizing factors (EDHFs)). A number of studies have provided evidence that this nitric oxide- and cyclooxygenase (COX)-independent endothelium-derived relaxing factor is a metabolite of the arachidonic acid cascade. It has been postulated that the unidentified EDHF hyperpolarized vascular smooth muscle cells by activating calcium-activated K+ channels (KCa), but the identity of the EDHF(s) has been debated.
Cytochrome P-450 (CYP) metabolites produced by the endothelium have been shown to have antihypertensive properties. Epoxyeicosatrienoic acids (EETs) are produced by the kidney and act to increase renal blood flow and promote sodium secretion. It has been proposed that the EETs are endothelium-derived hyperpolarizing factors (EDHFs). Additionally, EETs have been demonstrated to have profibrinolytic effects, to have anti-inflammatory actions, and to inhibit smooth vascular muscle cell migration. The corresponding diols. vic-dihydroxyeicosatrienoic acids (DHETEs), lack significant renal vascular dilator activity. DHETEs are generated from EETs by the action of a soluble epoxide hydrolase (sEH), and in a number of vascular systems, the diols either have decreased actions or are devoid of activity.
Several EETs have been analyzed with respect to their ability to function as an EDHF. In particular, 5,6-EET is an EDHF candidate because it decreases renal perfusion pressure in the Wistar-Kyoto and spontaneously hypertensive (SHR) rats. In addition, 11,12-EET and 14,15-EET are the two epoxide metabolites of arachidonic acid that most consistently demonstrate vascular smooth muscle cell-relaxing properties and other cardiovascular protective activities. 11,12-EET acts on preglomerular vascular smooth muscle cells to dilate the arteriole. In addition, this epoxide metabolite activates renal microvascular smooth muscle cell KCa channels and activates KCa channels in cerebral and coronary vascular smooth muscle cells as well. ADP ribosylation is one intracellular mechanism that has been demonstrated to activate KCa channels in coronary arteries. In addition, epoxides also have been shown to hyperpolarize platelets by activating KCa channels. Renal microvascular activation of KCa channels appears to be mediated by cAMP stimulation of protein kinase A because afferent arteriolar dilation to the sulfonamide analog of 11,12-EET was substantially reduced by protein kinase A inhibition. The KCa channel- and protein kinase A-mediated dilator actions of 11,12-EET on afferent arterioles are consistent with the concept that 11,12-EET is an EDHF. Besides arterial endothelial cells, epoxyeicosatrienoic acid (EET) generation has been demonstrated in brain astrocytes, cardiac myocytes, airway tissues, the gastrointestinal tract, pancreas, and kidney. Vasodilation to EETs has been observed in renal, mesenteric, cerebral, pulmonary, and coronary arteries
Abnornal regulation of kidney and vascular epoxide metabolites occurs in renal and cardiovascular diseases including, for example, type 1 and type 2 diabetes, hepatorenal syndrome, metabolic syndrome, insulin resistance syndrome, glomerullonephritis, hypertension, congestive heart failure, heart attack hypertensive heart disease, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease, and renal disease. The protective actions of the epoxide metabolites are diminished or lost in these disease states. Therefore, it would be advantageous to identify compounds that mimic the protective action of epoxide metabolites.
To date, various strategies have been employed for the treatment of renal and/or cardiovascular disease. For example, some researchers have focused on the role of soluble epoxide hydrolase (sEH) in renal and cardiovascular disease and inhibition of this enzyme as an avenue to increase EET levels. See, e.g., U.S. Pat. No. 6,890,925 Ingraham et al.; U.S. Publication No. 2006/0148744 to Hammock et al.; and Imig, 2005, Am. J. Physiol. Renal Physiol. 289:F496-F503. Although some methods have been achieved which effectively treat renal and cardiovascular disease, clearly more therapeutics are needed to treat a broader range of renal and/or cardiovascular diseases and conditions, as well as to increase the efficacy of the methods that already exist.
Therefore, what is needed in the art are new compounds and compositions for treating renal and/or cardiovascular diseases and conditions. What is also needed are methods for treating renal and/or cardiovascular diseases and conditions such as type 1 and type 2 diabetes, hepatorenal syndrome, metabolic syndrome, insulin resistance syndrome, glomerullonephritis, hypertension, congestive heart failure, heart attack, hypertensive heart disease, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease, and renal disease.